Document Report Card

ID: ALA1138528

Journal: J Med Chem

Title: Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists: reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect.

Authors: Sato N, Ando M, Ishikawa S, Jitsuoka M, Nagai K, Takahashi H, Sakuraba A, Tsuge H, Kitazawa H, Iwaasa H, Mashiko S, Gomori A, Moriya R, Fujino N, Ohe T, Ishihara A, Kanatani A, Fukami T.

Abstract: A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp(34)NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.

CiteXplore: 19459652

DOI: 10.1021/jm900110t